Gone for good.
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The ESMO says it has been removed. Ask CJ about it.
Yes, I was going to add that the trial was really about testing pemetrexed in place of paclitaxel
since both arms of the trial used avastin. I think the Roche angle is unfounded, at least from this info.
However, at the Chicago Symposium the late breaking Plenary just before Gerber's talk
was about the very same trial and abstract also withdrawn from the ESMO meeting!
At Chicago:
1:30 p.m. - 1:40 p.m.
LBPL1 A Randomized, Open-label, Phase 3, Superiority Study of Pemetrexed
(Pem)+Carboplatin (Cb)+Bevacizumab (B) Followed by Maintenance Pem+B
Versus Paclitaxel (Pac)+Cb+B Followed by Maintenance B in Patients (Pts) with
Stage IIIB or IV Non-squamous Non-small Cell Lung Cancer (Ns-Nsclc)
Jyoti Patel
1:40 p.m. - 1:50 p.m.
LBPL2 Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of
Bavituximab Plus Docetaxel in Patients with Previously Treated Locally Advanced
or Metastatic Non-Squamous Non-Small-Cell Lung Cancer (Top-line Results)
David Gerber
At Vienna:
LBA32 - A phase 3 superiority study of pemetrexed
(Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by
maintenance Pem+Bev versus paclitaxel (Pac)+Cb+Bev
followed by maintenance Bev in stage IIIB or IV nonsquamous
non-small cell lung cancer (NS-NSCLC): Overall
and age group results
Jyoti Patel, Chicago, IL, USA
LBA35 - Randomized, double-blind, placebo (P)-controlled
phase 2 trial of bavituximab (B) plus docetaxel (D) in patients
with previously treated locally advanced or metastatic nonsquamous
non-small-cell lung cancer
David Gerber, Dallas, TX, USA
I don't know. The trial with Avastin and pemetrexed wasn't a real success. I don't see a connection there.
Maybe just a coincidence, but Kurt Wallander would say there is no such thing.
The abstract was for the second-line NSCLC trial, not the first-line, so why would
triggering MOS for first-line result in withdrawing the abstract?
Maybe the MOS was triggered and they need to announce it before the 29th?
Maybe a partnership was also triggered by that event? Just guessing.
LBA35 was the name of the abstract which did appear in the program book, but has now been removed.
I don't know what LBA32 was, but wasn't ours.
Click on the link, it is right there. Bavi poster discussion abstract was removed.
http://www.esmo.org/events/vienna-2012-congress/abstract-submission.html
On the ESMO website now:
http://www.esmo.org/events/vienna-2012-congress/abstract-submission.html
Special Announcement:
Ahead of the top 48 abstracts (LBA and PR suffix) that will be released during the ESMO 2012 Congress, over 1,600 abstracts can now be found in the online, searchable program (above).
Please note that abstracts LBA32 and LBA35 have been removed from the program.
Why would the abstract be removed? Could it be that Peregrine needs to be free to
announce some data that would have been delayed until the poster discussion on Sept 29th?
Exactly, falling into the trap and letting yourself be manipulated for his purposes.
Just say NO.
Kipperdo, thanks for the offer, and to all the others who have offered. I have people staying at the same hotel who will give me a ride.
FTM
Do they provide lunch at the ASM? I received a private message suggesting a meeting after the ASM
to talk it over. I won't be leaving until Friday morning so I am open to that.
That is where I will be staying and I can be a designated driver as I don't drink much.
Sounds good. Anybody going there from near the airport and can give me a ride?
Bavi makes it into today's issue of NCI Cancer Bulletin.
http://www.cancer.gov/ncicancerbulletin/091812/page3#b
New Drug Improves Survival in Patients with Advanced Lung Cancer
Patients with advanced lung cancer who received the drug bavituximab lived twice as long as trial participants who did not receive the drug. These results , from a phase II trial, were presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology . Peregrine Pharmaceuticals, Inc., the drug’s manufacturer, sponsored the trial.
Bavituximab is a monoclonal antibody that targets a molecule called phosphatidylserine (PS) that is found in the membranes of cells throughout the body, including those that line blood vessels. In normal cells, PS is restricted to the inside of cell membranes, where it is inaccessible to antibodies. Under certain conditions, like those found in the stressful tumor microenvironment, PS moves to the outer surface of the cell membrane, explained the study’s principal investigator, Dr. David Gerber of the University of Texas Southwestern Medical Center. In the case of tumor blood vessels, this means that PS is exposed and accessible to antibodies in the blood.
Laboratory studies have shown that bavituximab can trigger the destruction of tumor blood vessels. The drug may also work by harnessing the immune system. Tumors supplied by blood vessels with exposed PS can evade an immune response. That’s because exposed PS normally marks cells that are in the process of dying, so the immune system ignores them. The researchers hoped to learn whether bavituximab, by binding to PS, would signal to the immune system to attack tumor blood vessels with exposed PS, explained Dr. Gerber.
In the double-blind, placebo-controlled trial, the researchers randomly assigned 117 patients to one of three treatment groups: docetaxel (Taxotere) plus placebo, docetaxel plus a low dose of bavituximab, or docetaxel plus a higher dose of bavituximab. All patients had previously received initial chemotherapy. The trial was unblinded 18 months after the first patient was enrolled.
The results showed differences in tumor shrinkage (15 and 18 percent of patients in the low and high bavituximab groups had their tumors shrink, versus 8 percent of those receiving docetaxel plus placebo) and progression-free survival (about 4.5 months in the two bavituximab arms, versus 3 months with docetaxel plus placebo).
The greatest differences were for overall survival; patients receiving docetaxel plus placebo lived an average of 5.6 months from the start of treatment, whereas patients receiving docetaxel plus the low or high dose of bavituximab lived for an average of 11 and 13 months, respectively.
These survival differences are not likely due to differences in treatment received after the trial, Dr. Gerber noted. Seeing a larger improvement in overall survival than in progression-free survival is unusual for drugs that target cancer cells directly, he added. Because the improvement in survival with bavituximab “is persistent and most pronounced after a few months,” that suggests that the therapeutic benefit may be caused, at least in part, by an immune response, he said.
The researchers are planning a phase III trial of bavituximab in a larger group of lung cancer patients. Bavituximab is also being tested in combination with other treatments in patients with breast, rectal, liver, and prostate cancer.
This could be a meeting where a poster on the I124-PGN650 trial could be presented.
http://www.snmmi.org/index.cfm?PageID=11789
Some really interesting stuff in the program.
drumstick, I don't know why your message was deleted??
The fact that the enrollment ramps up the way it does does not bother me. I think
probably it is pretty typical of trials. All that matters to me is the results of the trial.
I think RRdog had assumed a similar ramp in his projections of MOS.
RRdog can you comment? or Mojojo?
Bob (RCJ), I will probably want to take you up on your offer of a ride to the ASM from the hotel. Thanks.
Did everyone catch this from the slide in the Peregrine webcast on the second-line NSCLC trial,
"From October 2010 to October 2011, 121 enrolled at 40 global trial centers"
Yet the PR which announced the start of the trial was dated June 4, 2010, so it seems
that for almost 4 months no patients were enrolled. I wonder if this is typical of new trials
and whether it has also happened with the pancreatic trial. The ramp up in enrollment would
be definitely towards the end and would affect calculations of how long the PFS or MOS would be.
This is something RRdog remarked on way back.
CRPC trial suspended as trial moves to MUSC. As I reported earlier
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78018229
now shows up on ClinicalTrials.gov
This study has been suspended.(Pending lead institution transfer to MUSC.)
http://www.clinicaltrials.gov/ct2/show/NCT01335204?term=bavituximab+OR+Peregrine&rank=6
check out this rotating PET image
http://en.wikipedia.org/wiki/File:PET-MIPS-anim.gif
and this article
http://en.wikipedia.org/wiki/PET_scan
Sunstar, there is a difference between PET imaging and NIR imaging. The PET scan won't be done as the
patient is under the knife, as is possible the with NIR. The PET scan could be used before the operation
to determine the exact location of the tumor(s), and afterward. The phase I with I124-PGN650 will try to determine
the best schedule for administering the agent to maximize the signal when the PET scan is done.
Here again is my table for phase 3 pancreatic cancer trials. This is a really hard nut to crack. If Bavi can make
headway here it will be very exciting. Note that in this historical context the numbers from the Threshold
phase IIb trial just announced are nothing to get excited about, and statistically the survival was not significant,
but the PFS was (p=0.005). PFS was the primary endpoint, but was not independently verified.
"The primary efficacy analysis was performed based upon 149 investigator-assessed PFS events and,
per protocol, pooled data from the two gemcitabine plus TH-302 dose groups in comparison to gemcitabine alone."
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=77501263
I will be staying at the Best Western Plus - Orange County Airport North on Hotel Terrace Dr. There is a Hampton Inn,
Comfort Inn, Embassy Suites, Holiday Inn, La Quinta Inn, Quality Suites very nearby. I won't have a car so
I need a ride unless it is within walking distance. The Holiday Inn Santa Ana - Orange County Airport has a restaurant
http://www.holidayinn.com/hotels/us/en/santa-ana/jwaca/hoteldetail
Definitely a more positive take! I like it.
Maybe Dr. Evilevitch was homesick for Sweden and got tired of waiting? It seems like radioisotopes have a
hard time getting approved. Maybe they should try irradiation + bavi for GBM instead.
Jay Carlson told me there would be a guest speaker, but at the time he didn't know who it would be.
There will be some meetings of us iHub PPHM fans, maybe the evening before or after. I will be there.
Entdoc, I think Thorpe will win the Nobel some day too. It will likely be many years from now, but it will come.
It would be great if he were to speak at the annual shareholders meeting next month.
All this talk about first and second-line NSCLC differences gives me thought about what is going on with
the second-line trial. If you remember this post of mine
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=73652352
I still think there could be a synergy with docetaxel that results in these incredible interim MOS numbers.
That may be possible because of feedbacks in the tumor microenvironment. During the time of treatment
(6 3-week cycles) the combination of docetaxel + bavituximab might reverse the immunosuppressive tumor
microenvironment and allow the adaptive immune response to kick in. Once the treatment cycles are done
patients who did develop such a response now have at least a partial immunity to the recurrence of the disease.
That could explain the long survival times. So it could be particular to the docetaxel + bavi combo, but the same
could happen with other chemo combinations. What I am saying is that what is going on is more than
just the increased exposure of PS that does occur with radiation and chemo drugs. Without the synergy
maybe you get 50% increase in MOS over control, with the synergy you get 100+%. So it wouldn't surprise
me if some of the trials with bavi work much better than others, but it wouldn't necessarily depend on the
indication, but on the combo used. There is still a lot we don't understand about all of this, it is cutting edge stuff.
Just trying to think out of the box. It is a beautiful day outside so I am out of here!
I have been reading up on the imaging potential. Trying to connect a few dots.
This paper came out last year. It used a near-infrared (NIR) dye conjugated to the F(ab)2 fragment of PGN635,
now called PGN650, to image PS exposed in mouse glioma.
Near-infrared Optical Imaging of Exposed Phosphatidylserine in a Mouse Glioma Model.
Zhao D, Stafford JH, Zhou H, Thorpe PE.
FREE: http://www.ncbi.nlm.nih.gov/pubmed/22191000
This paper just came out. It shows how NIR imaging used during surgery can be used to detect residual
tumor at the margins of the wound. They use a non-specific NIR dye called ICG to detect the tumor cells.
Intraoperative Near-Infrared Imaging of Surgical Wounds after Tumor Resections Can Detect Residual Disease
Brian Madajewski, Brendan Judy, Anas Mouchli, Veena Kapoor, David Holt, May D. Wang, Shuming Nie, and Sunil Singhal
http://clincancerres.aacrjournals.org/content/early/2012/08/29/1078-0432.CCR-12-1188.abstract
Note that three of the above authors were also on the next paper which came out earlier this year,
with Thorpe as a co-author. Here they used bavi with surgery to prevent relapses from residual tumor cells.
Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory
intratumoral infiltrates and inhibits tumor relapses after surgery.
Judy BF, Aliperti LA, Predina JD, Levine D, Kapoor V, Thorpe PE, Albelda SM, Singhal S.
FREE: http://www.ncbi.nlm.nih.gov/pubmed/22577350
Now put the pieces together. You use NIR-PGN650, instead of ICG, specific for PS on tumor vasculature,
to detect the residual tumor real-time during the surgery to remove all the tumor. The PS will be upregulated
if radiation is used first on the tumor. So this is the idea. The timing is such that at the time of surgery there
will be maximum signal to noise ratio for imaging the tumor.
1) Use radiation on the tumor 48 hours before surgery
2) Inject NIR-PGN650 24 hours before surgery
3) During surgery use the NIR real-time detection system as shown in the second paper above to get
all the tumor which will be fluorescent with the NIR-PGN650 bound to all the tumor vasculature and the tumor cells.
This is a video showing how it is done, but here they are using ICG. ICG can not be conjugated to antibodies
because of its structure. The dye used in paper one above, IRDye800CW is made by Li-COR.
http://www.jove.com/video/2225/multispectral-real-time-fluorescence-imaging-for-intraoperative?id=2225
Here is a video about using 800CW in image-guided surgery.
http://www.licor.com/translational/index.jsp
Based on what reasoning? It might help if you could write a complete sentence.
Does a computer create these people and repeat the same thing over and over?
Using radiation does increase the amount of PS exposed. However, in the second-line NSCLC trial about 91%
of the patients had metastatic disease. Usually radiation is not used in these cases, but in earlier stages of the
disease. So future trials using radiation will most likely be in patients with stages 1-3, and then using bavi might
have the real potential of stopping transition to stage 4. There will still be a need for bavi plus chemo in the
stage 4 population. My guess is that they will use the 3 mg/kg dose in the phase 3 trial. A lower dose might work
very well with radiation in the future.
I think the trial size is just too small to really say anything about regional effects. With only about 40 patients per arm,
and assuming 50% are US and 50% not, there will be a lot of variability due to small sample size.
In addition, the issue here is moot since the MOA of bavi does not depend on the amount of expression of
certain cell receptors as in most targeted therapies, which might have a ethnic dependence. There
might be an underlying response to the chemo drug used which has an ethnic genetic dependence,
but since PS is increased on the tumor vasculature due to the conditions that exist because of the tumor itself
I don't see any reason bavi shouldn't work the same way on Asians, as non-Asians.
Given that Peregrine, and its partner, want to sell bavi in a global market I would think the best thing to
do is to run a trial with a balanced mixture of patients from around the world, at least from the largest potential markets,
so I find this whole argument pointless.
Anatomy of a Failure.
The discussions about phase 3 NSCLC trials that have failed even though the previous phase 2 NSCLC trial(s) were seemingly positive led me to a little more study. There is a message here. I had a look at the recent failure of the FORTIS-M trial evaluating talactoferrin in NSCLC.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
"Planegg/Munich (Germany), Princeton, NJ and Houston, TX, August 6, 2012 – Agennix AG (Frankfurt Stock Exchange: AGX) today announced that the FORTIS-M Phase III trial with talactoferrin alfa (talactoferrin) did not meet its primary endpoint of improving overall survival."
"The FORTIS-M trial is a randomized, double-blind, placebo-controlled Phase III trial evaluating talactoferrin plus best supportive care compared to placebo plus best supportive care in Stage IIIb/IV NSCLC patients whose disease has progressed following two or more prior treatment regimens. There were 742 patients enrolled in the trial from over 160 clinical sites in North America, Europe and the Asia/Pacific region."
"Median overall survival in the talactoferrin arm was 7.5 months compared to 7.7 months for placebo (hazard ratio 1.04, p-value 0.66)."
Rajesh Malik, M.D., Chief Medical Officer and Member of the Management Board, said: “We are extremely disappointed and surprised with today’s results, especially considering the earlier promising results we had seen in two randomized Phase II trials with talactoferrin alfa in non-small cell lung cancer."
Note that this phase 3 trial was for third-line, or fourth-line patients.
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Now let's look at the "promising" results from the two previous phase 2 trials. I am just going to look at the overall survival results, since that is what we are interested in.
Trial 1:
Journal of Thoracic Oncology, Volume 6, Number 6, June 2011. Digumarti et al.
A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral Talactoferrin in Combination with
Carboplatin and Paclitaxel in Previously Untreated Locally Advanced or Metastatic Non-small Cell Lung Cancer
N = 55 in the TLF arm, and N = 55 in the placebo arm. 100% Asian (Indian) patients.
In the ITT population, median OS increased from 8.5 months in the placebo arm to 10.4 months in the TLF arm (HR = 0.87; p = 0.26)
Note that this trial was for first-line NSCLC.
Trial 2:
Journal of Clinical Oncology, Volume 29, Number 31, November 1, 2011. Parikh et al.
Randomized, Double-Blind, Placebo-Controlled Phase II Study of Single-Agent Oral Talactoferrin in Patients With
Locally Advanced or Metastatic Non–Small-Cell Lung Cancer That Progressed After Chemotherapy
N = 47 in the TLF arm, and N = 53 in the placebo arm. 100% Asian (Indian) patients.
Both arms had about 75% second-line patients, and 25% third-line or more.
The median OS in the ITT population was 3.7 months (90% CI, 2.8 to 4.9 months) in the placebo arm and 6.1 months (90% CI, 4.7 to
8.4 months) in the TLF arm (HR, 0.68; 90% CI, 0.47 to 0.98). The one-tailed P = 0.04 by log-rank test met the primary end point with
the prospectively targeted level of statistical significance.
Note this trial was for second-line, or third-line patients
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So why was there surprise that the phase 3 trial failed when all three trials evaluated different patient groups?
Why didn't they do a phase 3 trial that duplicated the phase 2 trial that was a success?
When you hear about a phase 3 trial that failed, even though the phase 2 trial was supposedly a success, it pays to look a little more closely at the facts.
Here is the message to take from this:
Robert Garnick, PhD, Head of Regulatory Affairs at Peregrine. "A global Phase III trial designed very similarly to the robust design of this Phase II trial greatly increases bavituximab's likelihood of success."
The reality of what you all are arguing about.
http://well.blogs.nytimes.com/2012/09/13/the-trials-of-cancer-trials/?ref=health
All we know is the abstract title says about the same as the Chicago title did.
I assume they will just update the MOS status.
It is a poster that is being discussed by someone else, not an oral presentation.
It could fill in some more details.
See this:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=79158309
Colonel, very nice compilation of the data. Thanks.
Something like, a billion here, a billion there, pretty soon you are talking about real money.
Seems like that might apply to Peregrine in the future!
Genentech has a licensing deal with Peregrine for some technology involved in
production of antibodies for the PS-imaging platform. Potentially Peregrine will have
to pay Genentech $5 million. There really isn't anything else there. It is chicken feed.
I was just thinking that a deal with Genentech, which is a subsidiary of Roche, would
mean that the future payments could be eliminated, but as I said it is small change if
bavi is approved. I know Genentech has a state-of-the-art facility in Vacaville, CA for
producing tons of antibodies which could come in handy some day.